Preparation of chemical compounds

ABSTRACT

The present invention is directed to processes for the preparation of N-(3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-yl-oxycarbonyl-, (4S,5R)-4-[4-(2-methylthiazolo-4-methyloxy)-benzyl]-5-i-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidine.

BACKGROUND OF THE INVENTION

The human immunodeficiency virus (“HIV”) is the causative agent ofacquired immunodeficiency syndrome (“AIDS”), a disease characterized bythe destruction of the immune system, particularly of CD4⁺ T-cells, withattendant susceptibility to opportunistic infections, and its precursorAIDS-related complex (“ARC”), a syndrome characterized by symptoms suchas persistent generalized lymphadenopathy, fever and weight loss.

Among the drugs currently used to treat HIV infections in humans arethose that inhibit the HIV aspartyl protease enzyme. Drugs that are usedas protease inhibitors are, in general, chemically complex and aredifficult to prepare in a cost-effective and efficient manner. As aresult of the inherent complexity of these molecules, new and moreefficient methods for their preparation are of value.

N-(3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-yl-oxycarbonyl-,(4S,5R)-4-[4-(2-methylthiazolo-4-methyloxy)-benzyl]-5-1-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidine,described in WO 00/76961, is a compound of interest as a new therapeuticagent in the treatment of HIV infections and associated conditions.There exists a need to produce this compound in large quantities forclinical investigation of the safety and efficacy of the compound intherapy.

The present invention concern processes for the preparation of N-(3R,3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-yl-oxycarbonyl-,(4S,5R)-4-[4-(2-methylthiazolo-4-methyloxy)-benzyl]-5-i-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidine.

The present invention also features chemical compounds useful asintermediates in the preparation of compounds that may function asinhibitors of HIV aspartyl protease.

WO 00/76961 discloses processes that could be applied to the preparationof N-(3R, 3aS, 6aR)-hexahydrofaro[2,3-b]furan-3-yl-oxycarbonyl-,(4S,5R)-4-[4-(2-methylthiazolo-4-methyloxy)-benzyl]-5-i-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidine.These processes are not desirable for large-scale manufacture due to lowthroughput, slow filtrations, variable purity of intermediates andproduct, and potential difficulties with removal of intermediates fromreactors, long drying times, and reproducibility. Processes of thepresent invention reduce the number of operations and isolations, andare efficient, safe, and reproducible, thereby rendering the processesconducive to use in large-scale manufacture of N-(3R, 3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-oxycarbonyl-,(4S,5R)-4-[4-(2-methylthiazolo-4-methyloxy)-benzyl]-5-i-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidine.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides processes and compounds that are usefulin the preparation of N-(3R, 3aS,6aR)-hexahydrofaro[2,3-b]furan-3-yl-oxycarbonyl-,(4S,5R)-4-[4-(2-methylthiazolo-4-methyloxy)-benzyl]-5-i-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides processes and compounds that are usefulin the preparation of N-(3R, 3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-oxycarbonyl-,(4S,5R)-4-[4-(2-methylthiazolo-methyloxy)-benzyl]-5-i-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidine,a compound of formula (I).

The present invention features a process for the preparation of acompound of formula (1)

comprising

(a) treating a compound of formula (II)

with excess isobutylamine in an alcohol-containing solvent to form acompound of formula (III);

(b) treating a compound of formula (II) with a compound of formula (IV)

in the presence of an aqueous base to form a compound of formula (V);

(c) deprotecting a compound of formula (V) to form a compound of formula(VI)

(d) and coupling with a compound of formula (VII)

to form a compound of formula (I).

Alternatively, step (d) may be performed by coupling with a compound offormula (VIII)

to form a compound of formula (I).

Alternatively, step (d) may be performed by coupling with a compound offormula (IX)

to form a compound of formula (I).

Alternatively, step (b) may be performed in the presence of anon-aqueous base.

Optionally, the product of step (d) may be crystallized by treatment inan appropriate solvent, for example, isopropyl alcohol-water.

The present invention also features a process for the preparation of acompound of formula (I) comprising steps (a), (b), (c) and (d) abovewherein steps (a) and (b) are combined in a one-pot reaction to yield acompound of formula (V) which is isolated and in which steps (c) and (d)are combined in a one-pot reaction to yield a compound of formula (I)via a compound of formula (VI).

The combination of steps (a) and (b) in a one-pot process may becritical to the efficiency of the present invention. The standard methodof conducting step (a), in refluxing ethanol or isopropanol, was notconducive to its combination with step (b) due to reduced inefficienciesassociated with the necessity to exchange of all of the reactionsolvent. Very high temperatures necessary for the execution of thisreaction in non-alcoholic solvents, e.g. in toluene, is not advisabledue to the stability limits of a compound of formula (II). It was found,however, that a small amount of methanol accelerates step (a) even whendiluted with acetonitrile, a solvent with favorable properties for theazeotropic removal of methanol and this observation was exploited sothat steps (a) and steps (b) could be combined.

The combination of steps (c) and (d) in a one-pot process may becritical to the efficiency of the present invention. The solvent systemof tetrahydrofuran-water was identified as one which could accomplishall of the following: 1) solubilize a compound of formula (V) and themethane sulfonic acid salt thereof; 2) solubilize a compound of formula(VI) and the methane sulfonic acid salts thereof; 3) be used as a mediumfor step (c) 4) be used as a medium for step (d); 5) solubilize acompound of formula (I); and 6) be modified for an aqueous workup insuch a way that a solvent exchange to the crystallization solvent(isopropanol-water) could be accomplished efficiently.

The following abbreviations may be used in the specification:

-   -   g (grams);    -   L (liters);    -   μL (microliters);    -   mM (millimolar);    -   mmol (millimoles);    -   min (minutes);    -   mp (melting point);    -   MeOH (methanol);    -   THF (tetrahydrofuran);    -   HOAc (acetic acid);    -   CBZ (benzyloxycarbonyl);    -   DMAP (4-dimethylaminopyridine);    -   DIBAL (di-isobutylaluminum hydride);    -   MsOH (methane sulfonic acid)    -   Pd/C (palladium on carbon)    -   LC (liquid chromatography)    -   GC (gas chromatography)    -   MTBE (tert-butyl methyl ether)    -   IPAC (isopropyl acetate)    -   DCM (dichloromethane)    -   mg (milligrams);    -   mL (milliliters);    -   M (molar);    -   mol (moles);    -   rt (room temperature);    -   h (hours);    -   TLC (thin layer chromatography);    -   TEA (triethylamine);    -   AcOEt (ethyl acetate);    -   BOC (tert-butyloxycarbonyl);    -   Ac (acetyl);    -   NBS N-bromosuccinimide);    -   LAH (lithium aluminum hydride);

Step (a) may be carried out by reacting tert-butyl(1S)-2-{4-[(2-methyl-1,3-thiazol-4-yl)methoxy]phenyl}-1-[(2S)-oxiran-2-yl]ethylcarbamatewith an amine, preferably isobutylamine, in the presence of a suitablesolvent, preferably acetonitrile and methanol. The reaction isadvantageously carried out at (or near) reflux. The product of step (a),a compound of formula (III), may be isolated or taken directly to step(b).

Step (b) may be carried out by addition of a sulfonyl chloride,preferably 1,3-benzodioxole-5-sulfonyl chloride (Commercial supplier:SF-Chem P.O. Box 1964 CH-4133 Pratteln 1 Switzerland) in a suitablesolvent, preferably acetonitrile, while maintaining 25° C. withnon-aqueous base, preferably N-methylmorpholine, present during theaddition. If aqueous base, preferably sodium bicarbonate, is used, it isadded after the sulfonyl chloride addition while maintaining atemperature of about 25° C. The product of the reaction, a compound offormula (V), is crystallized in a suitable solvent, preferablyacetonitrile-water.

Step (c) may be carried out by deprotection of a compound of formula (V)by treatment with an acid, preferably methane sulfonic acid, in asuitable solvent, preferably THF-water.

Step (d) may be achieved by neutralization of the acid used in step (c)with a base, preferably triethylamine, treatment of the free-based,deprotected compound of formula (VII)[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate],and heating at (or near) reflux. Compounds of formula (VIII) [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-4-carbomethoxyphenyl carbonate],and (IX) [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-1N-benzotriazolecarbamate] may also be used. After an aqueous workup, the productsolution may be exchanged for a suitable solvent, preferablyisopropanol-water, and crystallized.

A compound of formula (II) may be made by treating tert-butyl(15)-2-[4-(benzyloxy)phenyl]-1-[(2S)-oxiran-2-yl]ethylcarbamate(Commercial supplier: Aerojet Fine Chemicals P.O. Box 1718 RanchoCordova, Calif. 95741) with a hydrogenation catalyst, preferablypalladium on carbon, a hydrogen source, preferably hydrogen gas, in asuitable solvent, preferably tetrahydrofuran at ˜25° C.: The catalystmay be removed by filtration and an alkylating agent, preferably4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (Commercialsupplier: Lancaster Synthesis Inc., P.O. Box 1000, Windham N.H.03087-9977), may be added followed by a source of iodide, preferablysodium iodide, and a base, preferably sodium tert-butoxide whilemaintaining a temperature in the range of 30-40° C. Finally a solutionof aqueous base, preferably sodium hydroxide, is added to close anyepoxide inadvertently opened by the iodide anion. The resulting solutionmay be washed with aqueous solutions, preferably pure water and sodiumchloride solution, and solvent exchanged to an appropriatecrystallization solvent, preferably heptane-ethyl acetate.

A compound of formula (VII) may be made from(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol by treatment in a suitablesolvent, preferably DCM-IPAC, with a base, preferably pyridine, and a4-nitrophenoxy carbonyl source, preferably 4-nitrophenyl chloroformate.The product compound may be isolated subsequent to aqueous washes,preferably with dilute hydrochloric acid and then sodium bicarbonatesolution, by solvent exchange into a suitable crystallization solvent,preferably isopropyl acetate, and crystallization.

A compound of formula (VIII) may be made from(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol by treatment in a suitablesolvent, with a base, preferably pyridine, and 4-carbomethoxyphenylchloroformate. The product compound may be isolated subsequent toaqueous washes, preferably with dilute hydrochloric acid and then sodiumchloride solution, by solvent exchange into a suitable crystallizationsolvent, preferably ethyl acetate, and crystallization.

A compound of formula (IX) may be made from(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol by treatment in a suitablesolvent, with N-methylmorpholine and 1H-1,2,3-benzotriazole-1-carbonylchloride. The product compound may be isolated by crystallization.

The present invention features a process illustrated by Scheme I:

-   1. MeCN, isobutylamine, MeOH-   2. MeCN, (IV), sodium bicarbonate (aq)-   3. THF-water, MsOH-   4. THF-water, TEA, (VII)-   5. DCM-IPAC, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol,    4-nitrophenyl chloroformate, pyridine

Reaction 2 of Scheme I may alternatively be MeCN, N-methylmorpholine,(IV).

The present invention features a process for the preparation of acompound of formula (I)

comprising:

(a) reacting a compound of formula (II)

with excess isobutylamine in an alcohol-containing solvent to form acompound of formula (III);

(b) reacting a compound of formula (III) with a compound of formula (IV)

in the presence of an aqueous base to form a compound of formula (V);

(c) deprotecting a compound of formula (V) and coupling with a compoundof formula (VII)

to form a compound of formula (I).

The present invention further features a process for the preparation of(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate ofthe formula

comprising reacting (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol) of theformula

with 4-nitrophenyl chloroformate in a suitable solvent to form(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate.

The present invention features(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate ofthe formula

made by the process described above. The specific conditions may becritical to the efficiency of the process for preparing(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate. Theuse of isopropyl acetate for the isolation permits a very high toleranceto the purity of the (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol) input(e.g. 70-95% purity), affording >98% purity for the product[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate]Furthermore, under the conditions exemplified, an inevitable byproduct,namely bis(4-nitrophenyl) carbonate, is both minimized during thereaction (to 10-15%) and substantially reduced (to <2%) during therecrystallization.

The following examples further describe and demonstrate particularembodiments within the scope of the present invention. The examples aregiven solely for illustration and are not to be construed as limitationsas many variations are possible without departing from spirit and scopeof the invention.

Unless otherwise noted, all starting materials were obtained fromcommercial suppliers and used without further purification.

Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions are conducted under an inertatmosphere at room temperature unless otherwise noted.

EXAMPLE 1 Preparation of tert-butyl(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl(isobutyl)amino]-2-hydroxy-1-{4-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzyl}propylcarbamate

A reaction vessel was charged with tert-butyl(1S)-2-{4-[(2-methyl-1,3-thiazol-4-yl)methoxy]phenyl}-1-[(2S)-oxiran-2-yl]ethylcarbamate(1.0 wt.) followed by acetonitrile (3.5 vol.), methanol (1.0 vol.), andisobutylamine (8.3 equiv., 2.1 vol.). The resulting mixture was heatedto reflux and held at reflux for 3 h. Acetonitrile (9.0 vol.) wascharged and distillate (9.0 vol., 6.8 wt.) was collected at atmosphericpressure. A second portion of acetonitrile (9.0 vol.) was charged anddistillate (9.0 vol., 6.9 wt.) was collected at atmospheric pressure.Acetonitrile (2.5 vol.) was charged and the reaction mixture was cooledto ˜25° C. A solution of 1,3-benzodioxole-5-sulfonyl chloride (1.1equiv., 0.62 wt) in acetonitrile (2 vol.) was charged while maintaininga temperature of ˜25° C. A solution of sodium bicarbonate (1.2 equiv.,0.26 wt.) in water (2.3 vol.) was charged while maintaining atemperature of ˜25° C. The resulting reaction mixture was stirred for 4h. Acetic acid (2.0 equiv., 0.29 vol.) was charged followed by water (10vol.) and the resulting slurry was stirred for 1 h. The solids arefiltered and washed with a solution of acetonitrile (2.5 vol.) in water(7.5 vol). The product was dried at ˜50° C. in a vacuum oven. The titleproduct (1.5 wt, 90%) was a light beige solid.

EXAMPLE 2 Preparation of N-(3R, 3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-oxycarbonyl-(4S,5R)-4-[4-(2-methylthiazolo-4-methloxy)-benzyl]-5-1-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidine

A reaction vessel was charged with tert-butyl(1S,2R)-3-[(1,3-benzodioxol-S-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-{4-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzyl}propylcarbamate(1.0 wt.), tetrahydrofuran (5.0 vol.), and water (0.05 vol.) and stirredat ˜25° C. The reaction vessel was then charged with methane sulfonicacid (3.0 equiv., 0.30 vol.), and the resulting mixture was heated over30 min to ˜50° C., stirred, and then heated over 30 min to reflux. Water(0.25 vol.) was added, the reaction mixture was cooled to ˜50° C., andtriethylamine (3.7 equiv., 0.80 vol.) was added followed by solid(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate.(1.05 equiv., 0.48 wt.). The resulting mixture was brought to reflux,and stirred for 3.5 h. The reaction mixture was cooled to ˜50° C. andtert-butyl methyl ether (3.0 vol.) was added. Maintaining ˜50° C., themixture was washed with water (2.1 vol.), 10% (by weight) aqueouspotassium carbonate (2×2.1 vol., 1.0 equiv) and 5% (by weight) aqueousacetic acid (2.1 vol., 1.1 equiv) At atmospheric pressure, the organicmixture was concentrated to ˜4.2 vol (i.e. ˜3.3 vol removed) and dilutedto the original volume with isopropyl alcohol (˜3.3 vol.) The mixturewas again taken to 4.2 vol and diluted to the original volume withisopropyl alcohol (−3.3 vol.). After a final concentration to 4.2 vol,isopropyl alcohol (9.5 vol.) and water (0.30 vol) was charged. Theresulting mixture heated to dissolve all solids, cooled to 50° C.,seeded with N-(3R, 3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-oxycarbonyl-,(4S,5R)-4-[4-(2-methylthiazolo-4-methyloxy)-benzyl]-5-i-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidinecrystals (0.01 wt), and held at 50° C. for 1 h (or until appreciablecrystallization has occurred. The resulting slurry was cooled to roomtemperature at 0.7° C./min (˜35 min). The solid product was filtered,washed with 50:50 isopropyl alcohol/heptane (4 vol.) and heptane (4vol.), and dried at ˜50° C. in a vacuum oven. The product (0.97 wt, 90%)was a light beige solid.

EXAMPLE 3 Preparation of ethyl 4,5-dihydrofaran-3-yl(oxo)acetate

A flask was charged with 2,3-dihydrofuran (0.77 wt, 1.5 eq.),triethylamine (0.82 wt, 1.1 eq.) and MTBE (4 vol). To this solution atroom temperature was added ethyl chlorooxoacetate (1 wt., 1 eq.)dropwise. During the addition the temperature rose and was kept below35° C. by external cooling (total addition time 1 h). After theaddition, the reaction was allowed to cool to room temperature, andstirred for 2 h. The reaction mixture was washed with water (3×2 vol.).The organic layer was concentrated at 30° C. to afford ethyl4,5-dihydrofuran-3-yl(oxo)acetate as an oil (76-89%).

EXAMPLE 4 Preparation of (+/−)-1-(4,5-dihydrofuran-3-yl)ethane-1,2-diol

A flask fitted with an addition funnel, stirrer and nitrogen inlet wascharged with lithium aluminum hydride (1M in THF, 5.8 vol, 1 eq.). Thereaction was cooled to 15° C. A solution of ethyl4,5-dihydrofuran-3-yl(oxo)acetate (1 wt., 1 eq.) in THF (4 vol) wasadded dropwise keeping the temperature between 15-20° C. (1 h totaladdition time). After the addition was complete, the reaction wasstirred at room temperature for 30 min and then cooled to −5° C. A 2:1solution of THF:water (I vol) was added slowly keeping the temperaturebelow 5° C. A 15% sodium hydroxide solution (1 vol) was added dropwise,followed by water (0.3 vol). Celite (0.33 wt) was added and theresulting slurry was stirred 1 h at room temperature, filtered, and thefiltercake was washed with tetrahydrofuran (total of 5 vol.) to producea filtrate containing the title compound.

EXAMPLE 5 Preparation ofrel-(3S,3aR)-3a-bromohexahydrofuro[2.3-b]furan-3-ol

The solution of (+/−)-1-(4,5-dihydrofuran-3-yl)ethane-1,2-diol fromExample 4 was cooled to ˜−10° C. and titrated with NBS (˜0.69 eq basedon ethyl 4,5-dihydrofuran-3-yl(oxo)acetate used in example 4, ˜0.94wt.). The titration was accomplished by monitoring the exothermassociated with the portionwise addition of NBS carried out over ˜1 h at˜10° C. The reaction mixture was stirred for another ˜30 min and wastreated with 10% sodium sulfite solution (6 vol.). The resultingsolution (a 3:1 diastereomeric mixture) was concentrated to about onehalf the original volume in vacuo at 35-40° C. and extracted with methyltert-butyl ether (5×5 vol.). The combined organics were washed withwater (5×5 vol.), and concentrated to an oil to afford3a-bromohexahydrofuro[2,3-b]furan-3-ol as a diastereomeric mixture of 95to 5 (˜40% yield from ethyl 4,5-dihydrofuran-3-yl(oxo)acetate. Thewashes were combined and extracted with ethyl acetate (2×10 vol). Theextracts, made up of a 3:1 mixture of diastereomers, were cycled throughthe above extraction process to isolate ˜10% additional product as a95:5 diastereomeric mixture. Overall yield was ˜50% (two steps).

EXAMPLE 6 Preparation of rel-(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ylacetate

Rel-(3S,3aR,6aR)-3a-bromohexahydrofuro[2,3-b]furan-3-ol (1 wt., 1 eq)(95:5 mixture of diastereomers, unresolved), THF (4.2 wt.), andtriethylamine (0.58 wt, 1.2 eq.) were charged to a reactor followed by aslurry of palladium on carbon (0.28 wt, 5% Pd/C, 50% water) in water(0.86 wt.). The mixture was subjected to hydrogen gas for ˜8 hours andthe catalyst was removed by filtration and washed with THF (2×1 wt.).The resulting solution was concentrated to approximately half the volumeand successively charged with ethyl acetate and concentrated toapproximately half the volume to reduce water levels. Dichloromethanewas charged (6.5 wt.) followed by triethylamine (0.58 wt., 1.2 eq.), andDMAP (0.005 wt., 0.01 eq.) and the mixture was cooled to ˜5° C. Aceticanhydride (0.58 wt., 1.2 eq.) was added over 30 min while keeping thetemperature at 5-10° C. The reaction mixture was warmed to ˜23° C. over1.5 h at which point the acetylation was complete. Methanol (0.076 wt.,0.50 eq.) was charged over 10 min while controlling the temperature at23-27° C. After an additional 30 min of stirring, the organic layer wassuccessively washed with water (2×2.5 wt.) and 3% HCl (aq) (2.5 wt.).The organic layer was concentrated to the title compound as a freeflowing oil.

EXAMPLE 7 Preparation of 3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol

A reactor was charged with (racemic)rel-(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl acetate (1.0 eq) and0.1N NaH₂PO₄ (pH=4, 3.0 vol). The resulting solution was adjusted to pH5.0 with 15% aq NaOH. Altus ChiroClec-PC (5.10×10⁻⁴ wt) was added, thereaction heated to 40° C., and the pH kept between 4.8 and 5.2 withperiodic addition of 15% aq NaOH. The reaction was followed by chiral GCuntil all of the undesired acetate[(3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl acetate] had beenhydrolyzed (˜3-5 h). The mixture was filtered through a small inlinefilter to remove the CLEC. The mixture was stirred for 15 min andallowed to settle. The layers were separated and the aqueous layer wasextracted with DCM (2 vol). The organic layers were combined and washwith water (2×2 vol) until the undesired alcohol[(3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol] was less than 3% in theorganic layer. The resulting organic solution of the desired acetate[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl acetate] was thenconcentrated at atmospheric to 1 vol. Methanol (2.0 vol) was added,followed by potassium carbonate (0.012 eq, 0.01 wt). The mixture wasstirred for ˜2-3 hours whereupon conversion to the the desired alcohol[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol)]was complete. Acetic acid(0.025 eq, 0.008 vol) was then added to neutralize the base and themixture was concentrated at atmospheric and reduced pressure to ˜1 vol.Isopropyl acetate (2 vol) was added and the solution was againconcentrated to ˜1 vol. Isopropyl acetate (2 vol) was again added andthe solution was concentrated to 1 vol, and analyzed for MeOH content.

EXAMPLE 8 Preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl4-nitrophenyl carbonate

A flask was charged with a solution of(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol)(1.0 eq) from Example 7.Isopropyl Acetate was added to bring the total weight to 5.7 wt (˜5vol). The reaction was cooled to 15° C. Pyridine (1.4 eq, 0.87 vol) wasadded producing a slight exotherm. The solution was cooled again to 15°C. A solution of 4-nitrophenyl chloroformate (1.3 eq, 2.02 wt) indichloromethane (7 vol) was added as rapidly as possible whilemaintaining the reaction temperature 15 +/−3° C. An additional portionof dichloromethane (2 vol) was used in the transfer. Once the additonwas complete, the reaction was warmed to 20° C. and stirred for 1 h. GCassay showed the level of residual(3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol) was acceptable. HPLC assayindicated the extent of bis(4-nitrophenyl)carbonate formation wasacceptable. Water (5 vol) was added and the layers were stirred 15 min,settled and separated. The organic phase was washed with 1N HCl (5 vol)and 5% aq sodium bicarbonate (5 vol). The organic solution was thenconcentrated at atmospheric to ˜5 vol. Isopropyl acetate (4 vol) wasadded, and the solution was cooled to 65° C. and seeded. The mixture wasaged at 65° C. for 30 min and the resultant slurry was then cooled to 0°C. over 1 h, and aged for 1 h. Filtration with an MTBE wash (2 vol)afforded a light powder. The material was assayed by HPLC to demonstratethat the level of bis(4-nitrophenyl)carbonate was less than 2%. Thetitle product was dried in vacuo at 40-60-C (70-78%).

EXAMPLE 9 Preparation of tert-butyl(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-{4-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzyl}propylcarbamate

A reaction vessel was charged with tert-butyl(1S)-2-{4-[(2-methyl-1,3-thiazol-4-yl)methoxy]phenyl}-1-[(2S)-oxiran-2-yl]ethylcarbamate(1.0 wt.) followed by acetonitrile (3.5 vol.), methanol (1.0 vol.), andisobutylamine (8.3 equiv., 2.1 vol.). The resulting mixture was heatedto reflux and held at reflux for 3 h. Acetonitrile (6.0 vol.) wascharged and distillate (6.0 vol., 4.6 wt.) was collected at atmosphericpressure. A second portion of acetonitrile (6.0 vol.) was charged anddistillate (7.0 vol., 5.5 wt.) was collected at atmospheric pressure.Acetonitrile (2.0 vol.) and N-methylmorpholine (1.3 eq, 0.37 vol) wascharged and the reaction mixture was cooled to ˜25° C. A solution of1,3-benzodioxole-5-sulfonyl chloride (1.1 equiv., 0.62 wt) was chargedwhile maintaining a temperature of ˜25° C. The resulting reactionmixture was stirred for 4 h. The solution was heated to 65° C. and water(2.5 vol) was charged maintaining 65° C. The solution was seeded withtert-butyl(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-{4-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzyl}propylcarbamate(0.01 wt) and aged for 0.5 h at 65° C., wherupon water (5 vol) wascharged again, maintaining the temperature at 65 IC. The resultingslurry is cooled to 25° C. and stirred for 1 h. The solids are filteredand washed with a solution of acetonitrile (0.5 vol.) in water (1.5vol). The product was dried at ˜50° C. in a vacuum oven. The titleproduct (1.6 wt, 95%) was a light beige solid.

EXAMPLE 10 Preparation of N-(3R, 3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-oxycarbonyl-,(4S,5R)4-[4-(2-methylthiazolo-4-methyloxy)-benzyl]-5-1-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidine

A reaction vessel was charged with tert-butyl(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-{4-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzyl}propylcarbamate(1.0 wt.), tetrahydrofuran (5.0 vol.), and water (0.3 vol.) and stirredat ˜25° C. The reaction vessel was then charged with methane sulfonicacid (3.0 equiv., 0.30 vol.), and the resulting mixture was heated over30 min to ˜50° C., stirred, and then heated over 30 min to reflux. Thereaction mixture was cooled to ˜50° C., and triethylamine (3.7 equiv.,0.80 vol.) was added followed by solid(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate.(1.05 equiv., 0.48 wt.). The resulting mixture was brought to reflux,and stirred for 3.5 h. The reaction mixture was cooled to ˜50° C. andtert-butyl methyl ether (3.0 vol.) was added. Maintaining ˜50° C., themixture was washed with water (2.1 vol.), 10% (by weight) aqueouspotassium carbonate (2×2.1 vol., 1.0 equiv) and 5% (by weight) aqueousacetic acid (2.1 vol., 1.1 equiv) At atmospheric pressure, the organicmixture was concentrated to ˜4.2 vol (i.e. ˜3.3 vol removed) and dilutedto the original volume with isopropyl alcohol (˜3.3 vol.) The mixturewas again taken to 4.2 vol and diluted to the original volume withisopropyl alcohol (˜3.3 vol.). After a final concentration to 4.2 vol,isopropyl alcohol (9.5 vol.) and water (0.30 vol) was charged. Theresulting mixture heated to dissolve all solids, cooled to 50° C.,seeded with N-(3R, 3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-oxycarbonyl-,(4S,5R)4-[4-(2-methylthiazolo-4-methyloxy)-benzyl]-5-1-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidinecrystals (0.01 wt), and held at 50° C. for 0.5 h (or until appreciablecrystallization has occurred. The resulting slurry was cooled to 35° C.at 0.5° C./min (˜30 min) and stirred for 1 h. The slurry was furthercooled to 0° C. at 1.0° C./min (˜35 min) and stirred for 1 h. The solidproduct was filtered, washed with cold isopropyl alcohol 2×2 vol.), anddried at ˜65° C. in a vacuum oven. The product (0.97 wt, 90%) was alight beige solid.

EXAMPLE 11 Preparation of(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-4-carbomethoxycarbonate

A flask was charged with a solution of 4-carbomethoxyphenylchloroformate (1.2 eq) in ethyl acetate (6 vol) and cooled with stirringto 5° C. A solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol)(1.0eq) from Example 7, pyridine (1.4 eq) and ethyl acetate (4 vol) wasadded slowly maintaining the temperature below 15° C. The reaction waswarmed to room temperature and stirred for 1.5 h while following by GC.When the reaction was deemed complete, it was quenched with water (4vol) and heated to 35° C. The layers were separated and the organicwashed with 1 NHCl (2×1 vol) and brine (1 vol). The solution was driedby adding ethyl acetate (2 vol) distilling off solvent (2 vol) atatmospheric. The solution was then cooled to room temperature andfiltered to remove bis-(4-carbomethoxyphenyl)-carbonate. The filtratewas concentrated further and the title compound crystallized usingheptane as an anti-solvent. The slurry was filtered, washing the cakewith heptane (2 vol). The cake was dried under vacuum at ambient. Thetitle compound was obtained as a beige solid.

EXAMPLE 12 Preparation of(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-1N-benzotriazole carbamate

A flask was charged with 1H-1,2,3-benzotriazole-1-carbonyl chloride (1.2eq) and dimethoxymethane. A solution of(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol)(1.0 eq) from Example 7,N-methylmorpholine (1.3 eq), and dimethoxyethane (0.25 vol) was addedslowly, with stirring, maintaining the temperature at 40° C. Thereaction was then aged at 40° C. for 1.5 h while following by GC. Oncethe reaction was deemed complete, it was cooled to 30° C. and water (2.5vol) was added. The solution was cooled to 20° C. slowly andcrystallization occurred. Added water (3.5 vol) slowly, cooled to 15°C., and stirred for 10 min. The slurry was filtered, washing the cakewith water (2.5 vol). The cake was then dried in the oven under vacuumat 60° C. (3R,3aS,6R)-hexahydrofuro[2,3-b]furan-3-yl-1N-benztrazolecarbamate was obtained as a beige solid.

1. A process for the preparation of a compound of formula (I)

comprising: (a) treating a compound of formula (II)

with excess isobutylamine in an alcohol-containing solvent to form acompound of formula (III)

(b) treating a compound of formula (III) with a compound of formula (IV)

in the presence of an aqueous base to form a compound of formula (V)

(c) deprotecting a compound of formula (V) to form a compound of formula(VI)

(d) coupling a compound of formula (VI) with a compound of formula (VII)

to yield a compound of formula (I).
 2. A a process for the preparationof a compound of formula (I) comprising steps (a), (b), (c) and (d)according to claim 1 wherein steps (a) and (b) are combined in a one-potreaction to yield a compound of formula (V) which is isolated and inwhich steps (c) and (d) are combined in a one-pot reaction to yield acompound of formula (I).
 3. A process for the preparation of a compoundof formula (I)

comprising: (a) treating a compound of formula (II)

with excess isobutylamine in an alcohol-containing solvent to form acompound of formula (III);

(b) treating a compound of formula (III) with a compound of formula (IV)

in the presence of an aqueous base to form a compound of formula (V)

(c) deprotecting a compound of formula (V) and coupling with a compoundof formula (VII)

to form a compound of formula (I).
 4. A process for the preparation of acompound of formula (I)

comprising: (a) treating a compound of formula (II)

with excess isobutylamine in an alcohol-containing solvent to form acompound of formula (III)

(b) treating a compound of formula (III) with a compound of formula (IV)

in the presence of an aqueous base to form a compound of formula (V)>

(c) deprotecting a compound of formula (V) to form a compound of formula(VI)

(d) coupling a compound of formula (VI) with a compound of formula (VI)

to yield a compound of formula (I).
 5. A process for the preparation ofa compound of formula (I) comprising steps (a), (b), (c) and (d)according to claim 4 wherein steps (a) and (b) are combined in a one-potreaction to yield a compound of formula (V) which is isolated and inwhich steps (c) and (d) are combined in a one-pot reaction to yield acompound of formula (I).
 6. A process for the preparation of a compoundof formula (I)

comprising: (a) treating a compound of formula (II)

with excess isobutylamine in an alcohol-containing solvent to form acompound of formula (III)

(b) treating a compound of formula (III) with a compound of formula (IV)

in the presence of an aqueous base to form a compound of formula (V)

(c) deprotecting a compound of formula (V) and coupling with a compoundof formula (VIII)

to form a compound of formula (I).
 7. A process for the preparation of acompound of formula (I)

comprising: (a) treating a compound of formula (II)

with excess isobutylamine in an alcohol-containing solvent to form acompound of formula (III)

(b) treating a compound of formula (III) with a compound of formula (IV)

in the presence of an aqueous base to form a compound of formula (V)

(c) deprotecting a compound of formula (V) to form a compound of formula(VI)

(d) coupling a compound of formula (VI) with a compound of formula (IX)

to yield a compound of formula (I).
 10. A process for the preparation ofa compound of formula (I) comprising steps (a), (b), (c) and (d)according to claim 7 wherein steps (a) and (b) are combined in a one-potreaction to yield a compound of formula (V) which is isolated and inwhich steps (c) and (d) are combined in a one-pot reaction to yield acompound of formula (I).
 11. A process for the preparation of a compoundof formula (I)

comprising: (a) treating a compound of formula (II)

with excess isobutylamine in an alcohol-containing solvent to form acompound of formula (III)

(b) treating a compound of formula (III) with a compound of formula (IV)

in the presence of an aqueous base to form a compound of formula (V)

(c) deprotecting a compound of formula (V) and coupling with a compoundof formula (IX)

to form a compound of formula (I).
 12. A process according to claim 7wherein the alcohol-containing solvent is acetonitrile-methanol.
 13. Aprocess according to claim 7 wherein the aqueous base is sodiumbicarbonate.
 14. A process according to claim 4 wherein step (b) isperformed in the presence of non-aqueous base.
 15. A process for thepreparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenylcarbonate of the formula

comprising reacting (3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol) of theformula

with 4-nitrophenyl chloroformate in a suitable solvent to form(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate. 16.(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate ofthe formula

made by the process according to claim
 15. 17. A compound of formula(VIII)


18. A compound of formula (IX)


19. A process for the preparation of a compound of formula (I)

comprising: (a) treating a compound of formula (II)

with excess isobutylamine in an alcohol-containing solvent to form acompound of formula (III)

(b) treating a compound of formula (III) with a compound of formula (IV)

in the presence of non-aqueous base to form a compound of formula (V)

(c) deprotecting a compound of formula (V) to form a compound of formula(VI)

(d) coupling a compound of formula (VI) with a compound of formula (IX)

to yield a compound of formula (I).
 20. A process according to claim 19wherein the non-aqueous base is N-methylmorpholine.
 21. A process forthe preparation of a compound of formula (I)

comprising: (a) treating a compound of formula (II)

with excess isobutylamine in an alcohol-containing solvent to form acompound of formula (III)

(b) treating a compound of formula (III) with a compound of formula (IV)

in the presence of a non-aqueous base to form a compound of formula (V)

(c) deprotecting a compound of formula (V) to form a compound of formula(VI)

(d) coupling a compound of formula (VI) with a compound of formula (VII)

to yield a compound of formula (I).
 22. A process according to claim 20wherein the non-aqueous base is N-methylmorpholine.
 23. A processaccording to claim 1 wherein the alcohol-containing solvent isacetonitrile-methanol.
 24. A process according to claim 1 wherein theaqueous base is sodium bicarbonate.